Relapse into drug-taking among abstinent addicts represents the major obstacle to successful long-term treatment of addiction. Exposure to people, places and objects associated with their drug-taking often precipitates renewed substance abuse. Human and animal research indicates exposure to drug-associated cues activates a set of interconnected brain regions (accumbens area, prefrontal cortex, amygdala) and elicits strong craving. Research from the investigator's laboratory has identified the specific neuron populations of this circuit that show increased gene expression when rodents seek drugs as a result of being exposed to contextual cues previously paired with cocaine delivery. More recently, the principal investigator has demonstrated that the long-term memory for such cues that predict cocaine delivery depends upon the extracellular signal-regulated kinase (ERK) pathway of the accumbens. Inhibitors of this ERK pathway (i.e., MEK inhibitors) infused into the core of the nucleus accumbens of animals immediately after they recall the cocaine-cue memory interfere with the reconsolidation of the cocaine-cue memory, such that animals show no preference for cocaine- associated contextual cues for at least two weeks after memory reactivation. The project's long-term objective is to characterize the role of the ERK signaling pathway in the accumbens-prefrontal cortex- amygdala circuit during reconsolidation of drug-cue memories. Four specific aims will provide novel information relevant to this objective: (1) to characterize more fully the ability of MEK inhibitors to block reconsolidation of memories for cocaine-paired contexts, (2) to investigate whether interference with the ERK pathway in the amygdala and prefrontal cortical regions has a similar effect on cocaine- cue memories as does accumbens inhibition, (3) to identify the specific cell populations in these brain regions expressing activated ERK during recall of cocaine-related memories, and (4) to investigate the contribution of dopamine and glutamate transmitter receptors, and of receptor tyrosine kinase transactivation, in cue-elicited activation of the accumbens ERK pathway. Relevance. A greater understanding of the neurobiology of reconsolidation of drug-cue memories holds the potential to provide new avenues for preventing relapse into substance abuse among the addicted population.